OVERALL-PROJECT SUMMARY/ABSTRACT Genetically defined in the 1990s, congenital disorders of glycosylation (CDG) consist of 130+ different inborn metabolism errors with overall incidence of ~>1:100,000. Thirty years later: there is no disease natural history data, no comprehensive patient registry, and no reliable screening for many CDG types. Furthermore, almost no therapy is available. We do have a strong patient association, committed clinicians, and a growing scientist group forming a virtual consortium, which closely collaborates to improve patient outcomes. We need prospective natural history data on health concerns to impact quality of life, validate disease biomarkers, and develop reliable diagnostics to increase clinical trial readiness. Our preliminary findings include retrospective natural history data, as well as data on novel biochemical biomarkers and techniques containing glycomics, which were established and validated in pilot trials for screening and diagnostics in CDG. The first clinical trials in specific CDG types started with dietary intervention, as is the most common approach in CDG therapy. Our collaborating group pioneered in these trials, most importantly in D- galactose therapy in PGM1-CDG. We also initiated the first (limited) PMM2-CDG natural history study, in parallel with the NIH single center CDG natural history study. Our nation-wide network of regional centers will further collaborate on diagnosis, follow up, treatment and clinical research in CDG. Our overreaching aims are a) establishing early reliable diagnosis b) increase diagnostic success and sensitivity, c) improve our knowledge on the natural history, d) find new biomarkers and e) develop therapies in congenital disorders of glycosylation. We will include all types of CDGs, focusing on three major biochemical disorder groups within multifaceted CDG: a) the most common form of CDG; PMM2-CDG, b) the group of potentially treatable disorders affecting protein galactosylation, and c) a defect from the new glycosylation disorder group (disorders of de-glycosylation)--NGLY1 deficiency. To achieve these milestones, we will apply cross-disciplinary, team-based clinical research to 1) define natural history, validate patient reported outcome and share knowledge on congenital disorders of glycosylation; 2) develop and validate new biochemical diagnostic techniques and therapeutic biomarkers for clinical trials; and 3) restore appropriate glycosylation to improve clinical symptoms and quality of life in disorders of glycosylation. Partners in our consortium have collaborated for more than a decade in finding solutions to complex problems in CDG biology, sharing knowledge, individualizing therapy, organizing patient conferences, and supporting physicians caring for CDG patients. We have improved patient care in this rare disease, but it is not enough. Leveraging on a nation-wide network, this proposal's aims begin to relieve decades of unresolved questions, address lack of knowledge, develop treatment and meet currently unmet patient need.